These studies will continue to be directed toward obtaining a more thorough understanding of platelet membrane events, involving fibrinogen and von Willebrand factor (vWF), underlying the formation of a hemostatic platelet plug and initiation of thrombotic lesions. This will be accomplished by investigating in detail the domains of fibrinogen (the essential plasma factor required for platelet aggregation) in regard to its interaction with platelet receptors. Our studies to date indicate that one of these recognition sites (binding domains) comprises the 12 amino acid residue sequence at the carboxy-terminal end of the Gamma chain (Gamma400-411). Although a synthetic peptide corresponding to this domain permitted us to construct a polyvalent molecule which can function as "artificial fibrinogen" supporting platelet aggregation, another binding domain located on the Alpha chain can enhance the fibrinogen-platelet interaction. The proposed studies represent a continued effort to map fibrinogen for platelet receptor recognition sites and to characterize, in considerably more detail, the cunterpart or complementary binding domains on the platelet membrane by using small synthetic peptides as specific probes. These studies will be extended further by studying the mechanism of switching on and off platelet membrane binding domains (receptors) for fibrinogen by ADP and cyclic AMP, respectively. Since the ADP-induced binding mechanism for fibrinogen is shared with von Willebrand factor, we will continue our investigation of the functional properties of this newly delineated by us common pathway. Correlation of the binding function of vWF involved in the ADP-dependent pathway with the structure of the binding domain of vWF will be attempted utilizing our successful approach with fibrinogen. The knowledge gained in these studies should not only contribute to a fuller understanding of the membrane events responsible for formation of a platelet hemostatic plug, but may also provide new approaches for diagnosis and management of clinical states of this deranged hemostatic mechanism manifest as thrombotic or bleeding complications. Development of a new class of "antireceptor" drug and conversely, new platelet aggregating "synthetic substitutes" of fibrinogen can evolve from this research.